Cyanoacylalkenylureas



United States Patent 2,729,669 CYANOACYLALKENYLUREAS Viktor Papesch,

Chicago, Ill., assignors to G. D. Searle 111., a corporation of IllinoisNo Drawing. Application October 31, 1951, Serial No. 254,196

7 Claims. (Cl. 260-4654) Morton Grove, and Elmer F. Schroeder, & Co.,Chicago,

The present invention is concerned with a new group of organic nitrilesand, more particularly, with the compounds of the general structuralformula wherein A is a lower alkylene radical and one of the radicals Rand R is a member of the class consisting of lower alkyl, lowerhydroxyalkyl, lower aralkyl, and lower aryl radicals, and the other is alower alkenyl radical.

The radical A is a lower, saturated, bivalent, aliphatic hydrocarbonradical such as methylene, ethylene, propylene, butylene, trimethylene,and tetramethylene.

Among the radicals which one of the substituents R and R may representare lower alkyl radicals such as methyl, ethyl, normal andbranch-chained propyl, butyl, amyl, and hexyl, lower cycloalkyl radicalsas cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, lower arylradicals such as phenyl, tolyl, and naphthyl, lower aralkyl radicals asbenzyl, phenethyl, and phenylpropyl, and lower hydroxyalkyl radicals ashydroxyethyl, hydroxypropyl, hydroxybutyl, and the like.

The other one of the radicals R and R is a lower alkenyl radical such as2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, and hexenyl as well as analkyl substituted derivative, thereof such as methallyl, ethallyl,methylcrotyl and the like.

The nitriles of this invention have been found to possess valuabletherapeutic properties, particularly be-' cause of their eflect on thecardiovascular and renal systems and their chemotherapeutic action.Further they are valuable intermediates for the production of othermedicinal agents such as uracils, xanthines and the like, as shown inour copending applications, Serial No. 198,028, filed November 28, 1950,now abandoned, of which the present application is acontinuation-in-part, and Serial No. 264,248, filed December 29, 1951,issued as U. S. Patent 2,650,922 On September 1, 1953.

The compounds of our invention may be prepared by a number of methods.One of the preferred procedures consists in the heating of a urea of thetype R-NH-CO-NH--R' with acetic anhydride and a cyanoalkanoic acid ofthe type NCA- -COOH for 30 to 200 minutes at 50-100" C. It has beenfound that the substitution, of this cyanoacyl group occurs primarily atthe nitrogen atom to which the smaller group is attached. Thus if R is aradical containing more carbon atoms than R, the substitution occursprimarily as follows: R-NH-CONH-R+NC-A-COOH R-NHCO-NR'-CO-ACN+H20 It theR and R groups are of similar size, both of the expected isomers will beobtained in considerable amounts.

2,729,669 Patented Jan. 3, 1956 ICC We have also developed new methodsfor preparing these compounds, wherein substituted cyanoacylamines ofthe type are condensed with isocyanates of the type R-N,=C=O

all symbols being defined as hereinabove. It will be apparent that inthis case it is immaterial whether the R group is larger or smaller thanthe R group. How ever, the yields obtained by this method are not asgood as those obtained with themethod mentioned above. flt may be anadvantage of this method that no mixtures are obtained. However, becauseof the similarityin activity usually observed with the two isomers, wehave found it practical to use the mixture obtained by the first methodabove in medicinal evaluations and in the synthesis of uracils.

On evaporation of the solvents used for the condensation under reducedpressure, the cyanoacylureas were usually obtained as syrups, but inseveral cases they crystallized readily. The syrups may be furtherpurified by high vacuum distillation.

In order to establish their structure the compounds derived froma-cyanoalkanoic acids were converted to the corresponding6-amino-l,2,3,4-tetrahydro-2,4-pyrimidinediones. This cyclization iseifected by heating with a dilute alkali solution. The position of thegroups R and R in the substituted pyrimidinediones was verified byalkylation of the l-monosubstituted uracils, the latter being derivedfrom the monosubstituted cyanoacylureas of the type To a solution ofparts of mono-allylurea in parts. of acetic anhydride, 85 parts ofcyanoacetic acid are added and the mixture is maintained at 65 C. for2.5 hours. The mixture is then distilled at 20 mm. pressure until asyrup remains. 50 parts of water are added to this syrup anddistillation is resumed. The resulting syrup is dissolved in 3 parts of96% ethanol at 60C., stirred with charcoal and filtered. 5 to 6 volumesof ether are added to the filtrate at 40 C. Upon cooling the N-cyanoacetyl N-allylurea precipitates. a filter and washed with ether.The white crystals melt at about l42-l44 C.

The N-cyanoacetyl-N'-allylurea is cyclized by dissolving in warm 10%sodium hydroxide solution and treating with a sufiicient amount of 70%sodium hydroxide to raise the pH to 10. The solution is maintained at 60C. for five minutes. After cooling the crystals are collected on afilter and recrystallized from water. 1-allyl-6-amino- 1,2,3,l-tetrahydro-2,4-pyrimidinedione is obtained in the form of whitecrystals melting at 270272 C. The 3 allylxanthine prepared from thispyrimidinedione melts at about '300-30l.5 C. i

parts of allylamine are mixed and maintained for one hour It iscollected on at 55 C. The mixture is then cooled and the precipitate isfiltered, washed with petroleum ether, and then with diethyl ether. Theresulting N-allyl-cyanoacetarnide, recrystallized from toluene, melts atabout-63'- 66- C.

400 parts of thisamide-and 460=parts of ethyl-'isocyanate in 3600 partsof toluene are heated at reflux temperature for 24 hours with "stirring.Afte'r cooling and standing the solution is seeded withN-allylcyanoacetamide and the unreacted material iscaused'toprecipitate. The filtrate is evaporated at 50 Cdin vaeuo to asyrup which crystallizesupon standing at C. Recrystallized from water,using charcoal as a clarifying agent, the white N-allyl-N-cyanoacetyl-N-ethylurea melts at about 8486 C.

In order to induce cyclization a sufficient amount of sodium hydroxideisadded to raise the pH to l0. Cyclization occurs with great violence.After cooling, the -l-ethyl-3-allyl6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione is filtered, washed withice water andrecrystallized from water, using charcoal as a decolorizingagent. After dehydration this-compound melts at about l42 144 C.although some sintering is observed at l32134 C.

Exam le 3 300 parts of N-ethyl-N-ally lurea are dissolved in 650 partsof acetic anhydride and 630 parts of glacial acetic acid. Then 190 partsof cyanoacetic acidare added and the mixture is maintained at 65C. for2-hours. Most of the solvent is distilled off at mm. pressure and 60 C.100 parts of Water are added to the syrup and the distillation isresumed. The remaining syrup consists principally ofN-cyanoacetyl-N-ethyl-Nallylurea and a smaller amountofN-cyanoacetyl-N-allyl-N'-ethylurea.

In order to effect ring closure parts of this syrup are dissolved in 50partsof 10% sodium hydroxide and the pH is adjusted to 10 by addition of70% sodium hydroxide. The mixture is maintained at 60 C. for 5 minutes.On cooling crystals separate which are collected on a filter. Thesecrystals, which containiabout 80% l-allyl- 3-ethyl-6-amino l,2,3,4tetrahydro-2,'4 pyrimidinedione and 20%1-ethyl-3-allyl-6-amino-'1,2,3;4=tetrahydro-2,4- pyrimidinedi'one, meltafter dehydration at about 132-133 C. The ethyl allyl xanthinederivativeprepared therefrom melts at about 182-185" C.

Example 4 185 parts of .isobutylamine are'di'ssolved in 900 parts ofbenzene and cooled in an ice bath while 200 parts of allyl isocyanateare added gradually. The temperature should not be permitted to riseabove 30 C. The benzene is removed by vacuum distillation and theN-allyl- N'-isobutylure'a crystallizes spontaneously. 38 parts ofthis'urea derivative are dissolved in l00parts of acetic anhydride. Tothis solution 27 parts of'cyanoacetic acid are added and the temperatureis maintained at -60 C. for 2 hours. The solvent is removed ascompletely as practical by vacuum distillation at 20 pressure and C,after which 75 parts of water are added and the solution isredistilledunder the same conditions until a syrup remains which contains a mixtureof N- cyanoacetyl- N-isobutyl-N'-allylurea and N-cyanoacetyl-N-allyl-N'-isobutylure'a. I V

In order to effect ring closure, this syrupy mixture is dissolved in anequal volume of 10% sodium hydroxide and the pH is adjusted to 10 byaddition of sodium hydroxide. The mixture is maintained at 70 C. jor 5minutes and upon cooling crystals separate. These crystals arerecrystallized twice "from 40-45% ethanol. The resulting white productconsists of the hydrates of 1 allyl '3 isobutyl 6 amino 1,2,3,4 7tetrahydro- 2,4-pyrimidinedione and of l-isobutyl 3 allyl-6-amino-1',2,3g4-tetrahydro 2,4-pyrimidinedione. The dehydrated mixture melts atabout 9297 C.

Example 5 30- parts of n-hexylam'ine in 70 parts of benzene aremaintained at about 20 C. while 25 parts of allyl isocyanate are slowlyadded. The product is evaporated in vacuo whereupon theN-hexyl-N'-allylurea crystallizes in long needles. The urea derivativethus obtained is reacted with 30 parts of cyanoacetic acid and parts ofacetic anhydride for two hours at 60 C. The solvent is removed by vacuumdistillation at 20 mm. and 60 C. as far as practical. The syrup isdiluted with water and vacuum distillation resumed. This process isrepeated and a thick syrup is obtained which consists of N-allyl-N-cyanoacetyl-N'-hexylurea and a small but significant amount ofN-hexyl-N-cyanoacetyl-N-allylurea.

This syrup is treated with 10% sodium hydroxide so as to raise the pHabove 10 at a temperature of about 70 C. The mixture consistingprimarily of l-hexyl-3-allyl-6-arnino-1,2,3,4-tetrahydro-2,4-pyrimidinedione and a smaller amount ofl-allyl-3-hexyl-6-amino-l,2,3,4-tetra hydro-2,4-pyrimidinedione does notcrystallize spontaneously. The S-nitroso derivative thereof is preparedby nitrosating in alcohol with sodium nitrite and acetic acid. Thenitroso derivative. recrystallized from 50% alcohol, melts at about l45C.

Example 6 20.pa'rts of phenyl isocya'nate are added 'dropwise' withstirring to a solution of 10 parts of -'all-ylarnine in 50 parts ofbenzene, the reaction mixture being maintained at a temperature below 25C. 'Evaporation'in vacuo yields the N-allyl-'N-phenylurea. The compoundthus obtained is treated with 19 part's' o'fcya'noacetic acid and 60parts of acetic anhydride for two hours at 60 C. Vacuum distillation at20 and 60" and crystallization yields a -mixture'con-sis'tiiig primarilyof N-allyl- N-cyanoacetyl-N-phenylu'rea and a smaller amount of N-phenylN-cy'anoacetyl-N allylurea; This mixture, recrystallized from alcohol;melts at about 1 14l l5 C.

In order to effect ring closure these crystals are treated with 10%sodium hydroxide solution to-raise the pH to l0. After heating at 7 5 C.for 5 minutes, the mixture is cooled and the precipitate collected on -afilter. Two successive recrystallizations from 50% alcohol yield whitecrystals melting at about 194 C. These crystals consist primarily of'l-phe'nyl-3-allyl-6 amino l-,2.3,4- tetrahydro-Z,4-pyrimidinedione butcontain an admixture of lallyl-3-phenyl-6 arnino 1,2,3,4tetrahydio-2A-pyrimidinedione.

Example 7 To a solution of 30 parts of 'benz yl'amine in parts ofbenzene maintained at -a temperature below 25 C., 25 parts of allylisocyanate are slowly added with stirring. The solvent is removed undervacuum. To the N-allyl- N'-ben'zylurea thus obtained, 30 parts ofcyanoacetic acid and 100 parts of acetic anhydride are addedand thesolution is heated at 60 C. for '2 hours. Vacuum distillation results inthe formation of a syrup. After addition of 50 .p'arts of water, vacuumdistillation is resumed and this process is repeated once more. Thesyrup thus obtained contains a mixture of N-allyl-N-cyanoacetyl-N'-benzylurea and N-b'enzyl-N-'cyanoacetyl-N'-allylurea.

In order to effect cyclizationthe pH is raised to 10 by addition of a10% solution of sodium hydroxide. The temperature is raised to 70 C.After 5 minutes the solution is cooled and the gummy precipitate isfiltered. On treatment with 50% ethanol the precipitate crystallizes'and recrystallization from 75% alcohol yields white crystals which meltat about 218-220" C. They consist primarily of l=benzyl'-3allyl=6=amino-1,2,3,4-tetrahydro- 2,4-pyrimidine'dione, but eentain anadmixture of l-allyl- 3 benzyl 6 amino 1,2,3,4 tetrahydro 2,*4-pyrimidinedione.

Example 8 To a'chilled solution'of 184 parts'of crotyl isocyanate in 700parts of benzene, 122 parts of B-amino'ethanol are added gradually withstirring, the temperature being maintained below 25 C. The solvent isremoved under vacuum. 240 parts of the N-(fi-hydroxyethyl) -N-crotylureathus obtained are reacted with 210 parts of cyanoacetic acid and 700parts of acetic anhydride for 2 hours at 60 C. The solvent is evaporatedin vacuo at 60 C. as far as practical. The residual syrup is dilutedwith an equal volume of water and vacuum distillation is resumed. Afterrepetition of this dilution and evaporation process, a syrupy mixture isobtained.

In order to effect cyclization this mixture is treated with a sufficientamount of potassium hydroxide to raise the pH to 10. The alkali is addedportionwise to prevent a rise in temperature above 70 C. Cyclization at60-70 C. is completed within a few minutes. Upon concentration andchilling, there precipitates a mixture of the isomers, in which the1-crotyl-3-(fl-hydroxyethyl) 6 amino 1,2,3,4 tetrahydro 2,4-pyrimidinedione predominates over the l-(fl-hydroxyethyl) 3 crotyl 6amino 1,2,3,4 tetrahydro 2,4- pyrimidinedione.

Example 9 194 parts of methallylurea are dissolved in 260 parts ofacetic anhydride and treated with 170 parts of cyanoacetic acid. Afterheating and stirring at 70-75 C. for one half hour or untilcrystallization occurs, 800 parts of hot water are curs. TheN-cyanoacetyl-N'-methallylurea thus obtained melts at about 143-145 C.after another recrystallization from water. Cyclization is effected bydissolving in 400 parts of 5% sodium hydroxide solution and treatingwith a suflicient amount of 70% sodium hydroxide to raise the pH toabout 10. After heating for one half hour at 75 C. the pH is lowered byaddition of dilute hydrochloric acid to about 4, and thel-methallyl-G-amino- 1,2,3,4-tetrahydro-2,4-pydimidinedione collected ona filter and recrystallized from dilute ethanol, using charcoal as aclarifying agent. The resulting pure crystals melt at about 266-268 C.

Example 10 To a cooled and stirred solution of 142 parts ofmethallylamine in 900 parts of benzene, 156 parts of ethyl isocyanateare added dropwise. Upon concentration in vacuum N-ethyl-N-methallylureais obtained.

260 parts of this urea derivative are dissolved in 500 parts of aceticanhydride and treated with 157 parts of cyanoacetic acid at 60 C. andheated at that temperature for 2 hours. The solution is thenconcentrated in vacuum to a syrup. the vacuum distillation is repeated.The remaining syrup contains a mixture of N-cyanoacetyl-N-ethyl-N-methaLlylurea and a small quantity of N-cyanoacetyl-N-methallyl-N-ethylurea.

This syrup is treated with sufiicient 20% sodium hydroxide solution toraise the pH to 10. A violent reaction occurs. The reaction mixture isdiluted with 50 parts of water, stirred, cooled and filtered. Thematerial collected on the filter is recrystallized from 10% ethanol toyield a mixture of l-methallyl-3-ethyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione and l-ethyl- 3methallyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione melting atabout 157-159 C.

Example 11 340 parts of the ethyl ester of p-cyanopropionic acid and 150parts of allylamine are mixed and maintained for 1 hour at 55 C. Themixture is then cooled and the precipitate is filtered and washed firstwith petroleum ether and then with diethyl ether. 132 parts of theresulting N-allyl-fl-cyanopropionamide and 135 parts of added. Uponcooling precipitation oc-' in 800 parts of toluene are heated at reethylisocyanate for 24 hours with stirring. After coolflux temperature ingand standing the unreacted mixture is seeded with N- 100 parts of waterare added and p allyl-fl-cyanopropionamide to precipitate the unreactedamide. The filtrate is evaporated to a syrup which contains theN-allyl-N-B-cyanopropionyl-N'-ethylurea of the structural formulaOHz==CH-CHr-N-COCHz-CH2-CN Q-NHCQH5 Since the nitrile group is removedby two carbon atoms from the next carbonyl group, it is obviouslyimpossible to cyclize this urea to a pyrimidine.

Example 12 A solution of 38 parts of N-allyl-N'-isobutylurea in 110parts of acetic anhydride is treated with 27 parts of acyanopropionicacid and the temperature is maintained at 60 C. for 2 hours. The solventis removed as completely as'practicable at 20 mm. pressure after which200 parts of water are added and the solution is redistilled in vacuountil a syrup remains which contains a mixture ofN-(ozcyanopropionyl)-N-allylN-isobutylurea and theN-(occyanopropionyl)-N-isobutyl-N-allylurea.

This syrup is dissolved in an equal volume of a 10% sodium hydroxidesolution and the pH is raised to 10 by addition of 70% sodium hydroxide.The mixture is maintained at C. for 5 minutes, then cooled to yield1-isobutyl-3-allyl-5-methyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione and 1-allyl-3-isobutyl-5-methyl-6-amino-1,2,3,4-tetrahydro-Z,4-pyrimidinedione. After two recrystallizationsfrom 50% ethanol using charcoal as a clarifying agent, white crystalsmelting at about 92-97 C. are obtained.

We claim:

1. A nitrile of the structural formula wherein R is a methallyl radical,and R is a lower alkyl radical containing less than 4 carbon atoms.

3. A nitrile of the structural formula CHz=CH--CH2-NHCONR'--CO-CHz-CNwherein R is a lower alkyl radical containing less than '4 carbon atoms.

4. N-ethyl-N-cyanoacetyl-N'-allylurea. 5. A nitrile of the structuralformula R-NHCONR'--COCH2CN wherein R is a lower alkyl radical containingless than 4 carbon atoms, and R is a methallyl radical.

6. A nitrile of the structural formula R-NHCO-N(CH2CH=CH2)-COCH2CNwherein R is a lower alkyl radical containing less than 4 carbon atoms.

7. N-allylN-cyanoacetyl-N-ethy1urea.

References Cited in the file of this patent UNITED STATES PATENTS2,313,498 Allen et a1 Mar. 9, 1943 2,553,022 Wallingford et a1 May 15,1951 2,598,936 Papesch et a1. June 3, 1952

1. A NITRILE OF THE STRUCTURE FORMULA